Organic compounds -- part of the class 532-570 series – Organic compounds – Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
2000-09-13
2001-05-15
Ramsuer, Robert W (Department: 1626)
Organic compounds -- part of the class 532-570 series
Organic compounds
Heterocyclic carbon compounds containing a hetero ring...
Reexamination Certificate
active
06232472
ABSTRACT:
BACKGROUND OF THE INVENTION
This application is directed to an improved process for making 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide. A general process is disclosed in U.S. Pat. No. 5,466,823 and Penning et al.,
J. Med. Chem.,
Vol. 40, pp. 1347-1365, 1997. The process described herein yields a product with a higher ratio of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide with respect to its regioisomer, a higher yield and greater degree of purity than the previously disclosed process. The compound is generally useful as a non-steroidal antiinflammatory agent.
Non-steroidal, antiinflammatory drugs (NSAIDs) exert most of their antiinflammatory, analgesic and antipyretic through an inhibition of prostaglandin G/H synthase, also known as cyclooxygenase. Initially, only one form of cyclooxygenase was known, this corresponding to cyclooxygenase-1 (COX-1) or the constitutive enzyme. More recently, a second inducible form of cyclooxygenase, COX-2, has been characterized. This enzyme is distinct from the COX-1 enzyme. COX-2 is rapidly and readily inducible by a number of agents including mitogens, endotoxin, hormones, cytokines and growth factors. The constitutive enzyme, COX-1, is responsible in large part for endogenous basal release of prostaglandins and hence is important in physiological functions, such as the maintenance of gastrointestinal integrity and renal blood flow. In contrast, COX-2, is mainly responsible for the pathological effects of prostaglandins where rapid induction of the enzyme would occur in response to such agents as inflammatory agents, hormones, growth factors, and cytokines.
A brief description of the potential utility of cyclooxygenase-2 inhibitors is given in an article by John Vane,
Nature,
Vol. 367, pp. 215-216, 1994, and in an article in
Drug News and Perspectives,
Vol. 7, pp. 501-512, 1994.
Thus, one object of the present invention is to provide a process that yields a product with a higher ratio of 4-[5-(4-methylphenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl]benzenesulfonamide with respect to its regioisomer.
Another object of the present invention is to provide a process with a higher yield and greater degree of purity. These and other objects will be apparent to those of ordinary skill from the teachings contained herein.
SUMMARY OF THE INVENTION
This invention encompasses a novel process for synthesizing the compound represented by formula I:
or a salt, hydrate or solvate thereof, wherein A represents H, halo, or methyl, and B represents CH
3
, CH
2
F, CHF
2
or CF
3
, comprising reacting a compound of formula II:
with a compound of formula III:
or a salt or hydrate thereof, in an amide solvent at a controlled temperature to produce a compound of formula I.
DETAILED DESCRIPTION OF THE INVENTION
This invention encompasses a novel process for synthesizing a compound represented by formula I:
or a salt, hydrate or solvate thereof, wherein A represents H, halo, or methyl, and B represents CH
3
, CH
2
F, CHF
2
or CF
3
, comprising reacting a compound of formula II:
with a compound of formula III:
or a salt or hydrate thereof, in an amide solvent at a controlled temperature to produce a compound of formula I.
In a preferred embodiment, the amide solvent is selected from N,N-dimethylformamide, N,N-dimethylacetamide, 1-methyl-2-pyrrolidinone, 1,3-dimethyl-3,4,5,6-tetrahydro-2(1H)-pyrimidinone and 1,1,3,3-tetramethylurea.
In another embodiment, the controlled temperature does not exceed about 30° C.
In yet another embodiment, the amount of the regioisomer of formula I in the product is about 0.5% or less, and the product yield is at least about 80%.
A preferred embodiment is that wherein the compound of formula I is about 99% pure.
Of particular interest are compounds of formula I produced as a solvate of the amide solvent. More particluarly, this invention encompasses recrystallizing the amide solvate of the compound of formula I from isopropanol and water to produce an unsolvated compound of formula I.
For the purposes of this specification, the term “amide solvent” refers to N,N-dimethylformamide, N,N-dimethylacetamide as well as the other solvents that are described above. Ethereal solvents are disclosed in some of the examples and tables for comparison purposes.
The term “controlled temperature” means a threshold reaction temperature under which the reaction temperature is mainatined. An example of a controlled temperature is about 30° C.
The term regioisomer refers to the following structure:
The points of attachment of the CF
3
group and the 4-B-phenyl group on the pyrazole ring are reversed.
REFERENCES:
patent: 5466823 (1995-11-01), Talley et al.
patent: 5475018 (1995-12-01), Lee et al.
patent: WO 96/37476 (1996-11-01), None
Penning, et al.,J. Med. Chem., vol. 40, pp. 1347-1365, 1997.
Clas Sophie-Dorothee
Dalton Chad
O'Shea Paul
Tillyer Richard D.
Wang Xin
Billups Richard C.
Merck Frosst Canada & Co.
Ramsuer Robert W
Rose David L.
Yuro Raynard
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